FSTL4

Summary

FSTL4 (follistatin like 4, HGNC:21389) is a protein-coding gene on chromosome 5q31.1, encoding Follistatin-related protein 4 (Q6MZW2).

Predicted to enable brain-derived neurotrophic factor binding activity and calcium ion binding activity. Predicted to be involved in cell differentiation and regulation of BMP signaling pathway. Predicted to act upstream of or within negative regulation of brain-derived neurotrophic factor receptor signaling pathway; negative regulation of collateral sprouting; and negative regulation of dendritic spine development. Predicted to be located in secretory granule. Predicted to be active in extracellular region.

Source: NCBI Gene 23105 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 152 total
• MANE Select transcript: NM_015082

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21389
Approved symbol	FSTL4
Name	follistatin like 4
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1061
Ensembl gene	ENSG00000053108
Ensembl biotype	protein_coding
Entrez	23105

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265342, ENST00000507112, ENST00000509525, ENST00000510685, ENST00000511375, ENST00000514998, ENST00000897473, ENST00000897474

RefSeq mRNA: 1 — MANE Select: NM_015082 NM_015082

CCDS: CCDS34238

Canonical transcript exons

ENST00000265342 — 16 exons

Exon	Start	End
ENSE00000803517	133220748	133220866
ENSE00002044875	133612325	133612541
ENSE00002084087	133196455	133199797
ENSE00002205065	133400738	133400986
ENSE00002215577	133603858	133603993
ENSE00002222448	133567186	133567219
ENSE00003465135	133249410	133249576
ENSE00003518961	133316459	133316652
ENSE00003530399	133225150	133225284
ENSE00003547543	133210191	133210298
ENSE00003547728	133233417	133233537
ENSE00003550418	133217229	133217378
ENSE00003590025	133201933	133202042
ENSE00003596145	133312654	133312777
ENSE00003630248	133224190	133224216
ENSE00003630927	133225658	133225819

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 89.09.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4000 / max 95.8392, expressed in 315 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63397	0.7936	191
63398	0.4887	139
63393	0.0857	34
63392	0.0241	12
63400	0.0078	2

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	89.09	gold quality
secondary oocyte	CL:0000655	82.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.59	gold quality
islet of Langerhans	UBERON:0000006	80.33	gold quality
prefrontal cortex	UBERON:0000451	78.34	gold quality
right frontal lobe	UBERON:0002810	78.00	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.96	gold quality
primary visual cortex	UBERON:0002436	77.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.91	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.53	gold quality
frontal cortex	UBERON:0001870	74.07	gold quality
nucleus accumbens	UBERON:0001882	73.53	gold quality
right hemisphere of cerebellum	UBERON:0014890	72.99	gold quality
Brodmann (1909) area 23	UBERON:0013554	72.94	gold quality
left testis	UBERON:0004533	72.74	gold quality
neocortex	UBERON:0001950	72.73	gold quality
lateral nuclear group of thalamus	UBERON:0002736	72.22	gold quality
right testis	UBERON:0004534	71.46	gold quality
skin of leg	UBERON:0001511	71.18	gold quality
cerebellar hemisphere	UBERON:0002245	70.62	gold quality
cerebellar cortex	UBERON:0002129	70.56	gold quality
right adrenal gland cortex	UBERON:0035827	70.05	gold quality
testis	UBERON:0000473	70.02	gold quality
anterior cingulate cortex	UBERON:0009835	70.02	gold quality
occipital lobe	UBERON:0002021	69.96	gold quality
adenohypophysis	UBERON:0002196	69.70	gold quality
cerebellum	UBERON:0002037	69.50	gold quality
cerebral cortex	UBERON:0000956	68.91	gold quality
pituitary gland	UBERON:0000007	68.85	gold quality
right adrenal gland	UBERON:0001233	68.55	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	91.07
E-HCAD-25	yes	84.35
E-ANND-3	yes	5.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

122 targeting FSTL4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3140-3P	99.88	68.47	2069

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fstl4	ENSDARG00000044319
mus_musculus	Fstl4	ENSMUSG00000036264
rattus_norvegicus	Fstl4	ENSRNOG00000006565

Paralogs (6): FSTL3 (ENSG00000070404), SPINK5 (ENSG00000133710), FST (ENSG00000134363), FSTL1 (ENSG00000163430), FSTL5 (ENSG00000168843), SPINK6 (ENSG00000178172)

Protein

Protein identifiers

Follistatin-related protein 4 — Q6MZW2 (reviewed: Q6MZW2)

Alternative names: Follistatin-like protein 4

All UniProt accessions (2): D6RHU5, Q6MZW2

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6MZW2-1	1	yes
Q6MZW2-2	2
Q6MZW2-3	3

RefSeq proteins (1): NP_055897* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR002350	Kazal_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050653	Prot_Inhib_GrowthFact_Antg	Family

Pfam: PF07648, PF13927

UniProt features (25 total): binding site 5, disulfide bond 5, domain 4, splice variant 3, sequence conflict 3, sequence variant 2, signal peptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6MZW2-F1	81.18	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 198; 187; 189; 191; 193

Disulfide bonds (5): 87–119, 93–112, 101–133, 270–321, 362–413

Glycosylation sites (1): 318

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_DENDRITIC_SPINE_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_COLLATERAL_SPROUTING, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION

GO Biological Process (6): cell differentiation (GO:0030154), regulation of BMP signaling pathway (GO:0030510), negative regulation of brain-derived neurotrophic factor receptor signaling pathway (GO:0031549), negative regulation of collateral sprouting (GO:0048671), negative regulation of dendritic spine development (GO:0061000), regulation of collateral sprouting (GO:0048670)

GO Molecular Function (4): calcium ion binding (GO:0005509), brain-derived neurotrophic factor binding (GO:0048403), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): extracellular region (GO:0005576), secretory granule (GO:0030141)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
collateral sprouting	2
cellular developmental process	1
BMP signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to growth factor stimulus	1
negative regulation of signal transduction	1
brain-derived neurotrophic factor receptor signaling pathway	1
regulation of brain-derived neurotrophic factor receptor signaling pathway	1
negative regulation of cell growth	1
negative regulation of developmental growth	1
regulation of collateral sprouting	1
negative regulation of axonogenesis	1
negative regulation of developmental process	1
dendritic spine development	1
regulation of dendritic spine development	1
regulation of developmental growth	1
regulation of axonogenesis	1
regulation of extent of cell growth	1
metal ion binding	1
neurotrophin binding	1
binding	1
cation binding	1
cellular anatomical structure	1
endomembrane system	1
secretory vesicle	1

Protein interactions and networks

STRING

758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FSTL4	FSHR	P23945	462
FSTL4	FSTL3	O95633	458
FSTL4	GDF9	O60383	453
FSTL4	BMP15	O95972	430
FSTL4	BMP10	O95393	418
FSTL4	WFIKKN1	Q96NZ8	418
FSTL4	BMP4	P12644	416
FSTL4	DAAM2	Q86T65	415
FSTL4	CHRDL2	Q6WN34	408
FSTL4	FST	P19883	404
FSTL4	CATSPERG	Q6ZRH7	398
FSTL4	TYW3	Q6IPR3	395
FSTL4	GDF15	P78360	376
FSTL4	ANKZF1	Q9H8Y5	368
FSTL4	DRC4	O95995	359

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ISG15	SURF4	psi-mi:“MI:0914”(association)	0.350
FSTL4	RPL23	psi-mi:“MI:0914”(association)	0.350
FSTL4	PLAU	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): KCMF1 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), RPL23 (Affinity Capture-MS), FSTL4 (Affinity Capture-MS), RPL23 (Affinity Capture-MS), KCMF1 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), LAMB2 (Affinity Capture-MS), METRNL (Affinity Capture-MS), MISP (Affinity Capture-MS), FGFR3 (Affinity Capture-MS), ABHD12 (Affinity Capture-MS), BMP1 (Affinity Capture-MS), PLAU (Affinity Capture-MS), TGFB1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0D3QS98, A0A0D3QS99, A4D0V7, C5H5C4, F6Q1T7, O70309, O75354, P17405, P18084, P18424, P22413, P50747, P52850, P58242, P61642, P80747, Q04519, Q0VBD0, Q0VD19, Q13219, Q52KP5, Q58CQ9, Q5QQ51, Q5STE3, Q64687, Q6DFZ6, Q6KFX9, Q6MZW2, Q6P988, Q6UWX4, Q6YGZ1, Q6ZXD2, Q71RP1, Q812F8, Q8BJQ9, Q8C1F4, Q8C419, Q8N5D6, Q8N6G5, Q8R116

Diamond homologs: A0N0X6, A2AJ76, A2CG49, A4IGL7, A4IIW9, B3NS99, B4GBH0, B4HNW4, B4KPU0, B4MR28, B4P5Q9, B4QC63, G5EBF1, O75325, O95428, P0C6S8, P11627, P12960, P22063, P28685, P32004, P97924, Q02246, Q07409, Q09024, Q12860, Q290N5, Q32Q07, Q3UQ28, Q3URE9, Q3V1M1, Q5R482, Q61330, Q61809, Q62682, Q62845, Q63198, Q66HV9, Q69Z26, Q6AWJ9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

152 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	116
Likely benign	20
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

4841 predictions. Top by Δscore:

Variant	Effect	Δscore
5:133199793:CAAAC:C	acceptor_gain	1.0000
5:133199795:AAC:A	acceptor_gain	1.0000
5:133199796:AC:A	acceptor_gain	1.0000
5:133199796:ACC:A	acceptor_loss	1.0000
5:133199797:CC:C	acceptor_gain	1.0000
5:133199798:C:CC	acceptor_gain	1.0000
5:133199799:T:G	acceptor_loss	1.0000
5:133201927:TCTCA:T	donor_loss	1.0000
5:133201928:CTCA:C	donor_loss	1.0000
5:133201929:TCA:T	donor_loss	1.0000
5:133201930:CA:C	donor_loss	1.0000
5:133217225:GTACC:G	donor_loss	1.0000
5:133217227:A:AG	donor_loss	1.0000
5:133217228:CCTG:C	donor_loss	1.0000
5:133217379:C:CA	acceptor_loss	1.0000
5:133217380:T:G	acceptor_loss	1.0000
5:133220746:A:AC	donor_gain	1.0000
5:133220747:C:CC	donor_gain	1.0000
5:133220747:CATA:C	donor_gain	1.0000
5:133220747:CATAG:C	donor_gain	1.0000
5:133220751:G:C	donor_gain	1.0000
5:133224259:C:CT	acceptor_gain	1.0000
5:133224260:A:T	acceptor_gain	1.0000
5:133225149:CGGGT:C	donor_gain	1.0000
5:133249403:GACTT:G	donor_loss	1.0000
5:133249404:ACTT:A	donor_loss	1.0000
5:133249405:CTT:C	donor_loss	1.0000
5:133249406:TTACA:T	donor_loss	1.0000
5:133249407:TA:T	donor_loss	1.0000
5:133249408:A:AC	donor_gain	1.0000

AlphaMissense

5533 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:133225231:A:C	Y411D	1.000
5:133225715:A:G	W374R	1.000
5:133225715:A:T	W374R	1.000
5:133225211:A:C	N417K	0.999
5:133225211:A:T	N417K	0.999
5:133225218:G:T	A415D	0.999
5:133225223:G:C	C413W	0.999
5:133225224:C:G	C413S	0.999
5:133225224:C:T	C413Y	0.999
5:133225225:A:G	C413R	0.999
5:133225225:A:T	C413S	0.999
5:133225713:C:A	W374C	0.999
5:133225713:C:G	W374C	0.999
5:133225750:C:G	C362S	0.999
5:133225751:A:G	C362R	0.999
5:133225751:A:T	C362S	0.999
5:133225179:A:G	L428P	0.998
5:133225212:T:A	N417I	0.998
5:133225219:C:G	A415P	0.998
5:133225269:A:G	L398P	0.998
5:133225739:C:G	G366R	0.998
5:133225749:G:C	C362W	0.998
5:133225750:C:T	C362Y	0.998
5:133225756:A:G	L360P	0.998
5:133249458:C:A	W282C	0.998
5:133249458:C:G	W282C	0.998
5:133225213:T:A	N417Y	0.997
5:133225230:T:G	Y411S	0.997
5:133225231:A:T	Y411N	0.997
5:133225237:C:A	G409W	0.997

dbSNP variants (sampled 300 via entrez): RS1000002624 (5:133256767 T>A,C), RS1000003518 (5:133832734 G>T), RS1000006213 (5:133597358 T>C,G), RS1000006902 (5:133468073 A>C), RS1000010426 (5:133762416 G>T), RS1000018034 (5:133755379 G>T), RS1000018338 (5:133802814 G>A,T), RS1000020894 (5:133209335 T>G), RS1000026893 (5:133224866 C>A), RS1000033431 (5:133761961 G>A), RS1000043923 (5:133507157 G>A,T), RS1000045700 (5:133211233 T>A,C), RS1000052159 (5:133413726 A>G), RS1000054400 (5:133421233 C>T), RS1000059100 (5:133385160 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001356_27	Gout	1.000000e-07
GCST001423_1	Hypertension	9.000000e-08
GCST003075_123	Cognitive decline rate in late mild cognitive impairment	7.000000e-06
GCST003075_40	Cognitive decline rate in late mild cognitive impairment	9.000000e-07
GCST003263_30	Post bronchodilator FEV1 in COPD	2.000000e-06
GCST003476_5	Eyebrow thickness	3.000000e-06
GCST003808_3	Non-response to selective serotonin reuptake inhibitors and depression	1.000000e-06
GCST004746_31	Small cell lung carcinoma	2.000000e-06
GCST007843_9	Rheumatoid arthritis	2.000000e-09
GCST008074_151	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	9.000000e-11
GCST008074_53	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-07
GCST008075_78	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-08
GCST008076_48	Triglyceride levels	1.000000e-06
GCST008083_118	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-11
GCST008083_24	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-07
GCST008084_53	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-07
GCST008087_112	Triglyceride levels in current drinkers	9.000000e-06
GCST008087_20	Triglyceride levels in current drinkers	7.000000e-09
GCST010173_148	Triglyceride levels	3.000000e-09
GCST011973_5	Colorectal cancer	3.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0004314	forced expiratory volume
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases methylation	3
sodium arsenite	affects methylation, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Tretinoin	affects cotreatment, decreases expression	2
propionaldehyde	increases expression	1
bisphenol A	decreases methylation, affects cotreatment, increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Catechin	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.